DESCRIPTION: Despite many major advances in AIDS research, including the development of anti-retroviral drugs that suppress virus replication and greatly reduce the mortality and morbidity of HIV infection, a treatment that can cure the infection is still not available. Indeed, combination antiretroviral therapy (ART) must be taken for life, thus posing significant challenges in terms of costs and clinical safety, and interruption of therapy results in a rapid rebound of viremia in the majority of HIV-infected individuals. To this end, new approaches are required to eradicate the reservoirs of latently infected cells that persist during ART and are the source of virus reactivation when therapy is interrupted. The overarching Aim of this proposal is to explore the therapeutic potential of type I interferon (IFN-I), that activates a very potent natural antiviral molecular system, in reducing the reservoirs of virus-infected cells that persist under ART. In the R21 phase of this grant application we propose to use the existing, well-established nonhuman primate model of SIVmac infection of rhesus macaques (RMs) to evaluate, in a relatively small pilot study, the potential impact of pegylated IFN-?2a (pIFN-?2a) on the overall size, anatomic location, and cellular distribution of the reservoirs of latently infected cells in ART-treated, SIV-infected RMs. We will use this very robust model to investigate directly in vivo and in multiple organs (i.e., blood, lymph nodes, spleen, mucosal tissues, etc.) and cell types (i.e., memory CD4+ T cell subsets and macrophages) whether and to what extent pIFN-?2a administration enhances the effect of ART on the virus reservoir. The results of the studies proposed in the R21 part of this application will pave the way for further experiments, to be conducted in the R33 phase of this proposal, in which we will test, in a larger cohort of SIV-infected RMs treated with long-term ART and exhibiting full suppression of virus replication, the effect of two consecutive cycles of pIFN-?2a treatment on (i) the size of the persisting reservoirs of latently infected cells, and (ii) the time of rebound of plasma viremia afer ART interruption. We believe that the proposed studies will provide unprecedented insights into the role of type I interferon in reducing and/or altering the cellular and anatomic distribution of the persistent virus reservoirs of latently infected cells in an in vivo model of pathogenic lentivral infection in which active virus replication is fully suppressed by ART. We believe that these results will be crucial to determine the potential of IFN-I therapy in HIV-infected individuals.